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[[ | ==Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 3-((4 -(trifluoromethyl)phenyl)amino)benzoic acid== | ||
<StructureSection load='4dbu' size='340' side='right' caption='[[4dbu]], [[Resolution|resolution]] 2.53Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4dbu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DBU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DBU FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BT9:3-{[4-(TRIFLUOROMETHYL)PHENYL]AMINO}BENZOIC+ACID'>BT9</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dbs|4dbs]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKR1C3, DDH1, HSD17B5, KIAA0119, PGFS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dbu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dbu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dbu RCSB], [http://www.ebi.ac.uk/pdbsum/4dbu PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Castrate resistant prostate cancer (CRPC) is associated with increased androgen receptor (AR) signaling often brought about by elevated intratumoral androgen biosynthesis and AR amplification. Inhibition of androgen biosynthesis and/or AR antagonism should be efficacious in the treatment of CRPC. AKR1C3 catalyzes the formation of potent AR ligands from inactive precursors and is one of the most upregulated genes in CRPC. AKR1C3 inhibitors should not inhibit the related isoforms, AKR1C1 and AKR1C2 that are involved in 5alpha-dihydrotestosterone inactivation in the prostate. We have previously developed a series of flufenamic acid analogs as potent and selective AKR1C3 inhibitors [Adeniji, A. O. et al., J. Med. Chem.2012, 55, 2311]. Here we report the X-ray crystal structure of one lead compound 3-((4-(trifluoromethyl)phenyl) amino)benzoic acid (1) in complex with AKR1C3. Compound 1 adopts a similar binding orientation as flufenamic acid, however, its phenylamino ring projects deeper into a subpocket and confers selectivity over the other AKR1C isoforms. We exploited the observation that some flufenamic acid analogs also act as AR antagonists and synthesized a second generation inhibitor, 3-((4-nitronaphthalen-1-yl)amino)benzoic acid (2). Compound 2 retained nanomolar potency and selective inhibition of AKR1C3 but also acted as an AR antagonist. It inhibited 5alpha-dihydrotestosterone stimulated AR reporter gene activity with an IC(50)=4.7muM and produced a concentration dependent reduction in androgen receptor levels in prostate cancer cells. The in vitro and cell-based effects of compound 2 make it a promising lead for development of dual acting agent for CRPC. To illuminate the structural basis of AKR1C3 inhibition, we also report the crystal structure of the AKR1C3.NADP(+).2 complex, which shows that compound 2 forms a unique double-decker structure with AKR1C3. | |||
Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer.,Chen M, Adeniji AO, Twenter BM, Winkler JD, Christianson DW, Penning TM Bioorg Med Chem Lett. 2012 Mar 29. PMID:22507964<ref>PMID:22507964</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[ | *[[Prostaglandin F synthase|Prostaglandin F synthase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Chen, M | [[Category: Chen, M]] | ||
[[Category: Christianson, D W | [[Category: Christianson, D W]] | ||
[[Category: Penning, T M | [[Category: Penning, T M]] | ||
[[Category: Winkler, J D | [[Category: Winkler, J D]] | ||
[[Category: Akr1c3 selective inhibitor]] | [[Category: Akr1c3 selective inhibitor]] | ||
[[Category: Castrate resistant prostate cancer]] | [[Category: Castrate resistant prostate cancer]] | ||
Revision as of 19:48, 9 December 2014
Crystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 3-((4 -(trifluoromethyl)phenyl)amino)benzoic acidCrystal structure of human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) in complex with NADP+ and 3-((4 -(trifluoromethyl)phenyl)amino)benzoic acid
Structural highlights
Publication Abstract from PubMedCastrate resistant prostate cancer (CRPC) is associated with increased androgen receptor (AR) signaling often brought about by elevated intratumoral androgen biosynthesis and AR amplification. Inhibition of androgen biosynthesis and/or AR antagonism should be efficacious in the treatment of CRPC. AKR1C3 catalyzes the formation of potent AR ligands from inactive precursors and is one of the most upregulated genes in CRPC. AKR1C3 inhibitors should not inhibit the related isoforms, AKR1C1 and AKR1C2 that are involved in 5alpha-dihydrotestosterone inactivation in the prostate. We have previously developed a series of flufenamic acid analogs as potent and selective AKR1C3 inhibitors [Adeniji, A. O. et al., J. Med. Chem.2012, 55, 2311]. Here we report the X-ray crystal structure of one lead compound 3-((4-(trifluoromethyl)phenyl) amino)benzoic acid (1) in complex with AKR1C3. Compound 1 adopts a similar binding orientation as flufenamic acid, however, its phenylamino ring projects deeper into a subpocket and confers selectivity over the other AKR1C isoforms. We exploited the observation that some flufenamic acid analogs also act as AR antagonists and synthesized a second generation inhibitor, 3-((4-nitronaphthalen-1-yl)amino)benzoic acid (2). Compound 2 retained nanomolar potency and selective inhibition of AKR1C3 but also acted as an AR antagonist. It inhibited 5alpha-dihydrotestosterone stimulated AR reporter gene activity with an IC(50)=4.7muM and produced a concentration dependent reduction in androgen receptor levels in prostate cancer cells. The in vitro and cell-based effects of compound 2 make it a promising lead for development of dual acting agent for CRPC. To illuminate the structural basis of AKR1C3 inhibition, we also report the crystal structure of the AKR1C3.NADP(+).2 complex, which shows that compound 2 forms a unique double-decker structure with AKR1C3. Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer.,Chen M, Adeniji AO, Twenter BM, Winkler JD, Christianson DW, Penning TM Bioorg Med Chem Lett. 2012 Mar 29. PMID:22507964[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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